Role of indoleamine 2,3-dioxygenase in an inflammatory model of murine gingiva.

BACKGROUND AND OBJECTIVE: Indoleamine 2,3-dioxygenase (IDO) is one of the major pathways for metabolism of tryptophan in a variety of cells, including immune cells. Increasing evidence indicates that IDO is a critical player in establishing the balance between immunity and tolerance and ultimately in the maintenance of homeostasis. By inducing inflammation in gingival tissue, we tested the hypothesis that IDO is a pivotal player in regulating the immune and inflammatory responses of gingiva. MATERIAL AND METHODS: We utilized the IDO knockout mouse model in conjunction with lipopolysaccharide (LPS)-induced inflammation. Accordingly, wild-type and IDO knockout mice were injected with LPS or vehicle in the anterior mandibular gingiva, twice over a 2-wk period, which was followed by procurement of gingival tissue for histopathology and preparation of tissue for flow cytometry-based studies. RESULTS: Clinical and histological examinations revealed a marked adverse impact of IDO deficiency on gingival inflammation. These observations were consistent with a more marked increase in the number of cells positive for the proinflammatory cytokine interleukin (IL)-17, but no significant change in the number of cells positive for the anti-inflammatory cytokine IL-10, in LPS-treated IDO knockout mice. Consistent with the more marked proinflammatory impact of IDO deficiency, the percentage of regulatory T cells was much reduced in gingival tissue of LPS-treated IDO knockout mice than in gingival tissue of wild-type mice. These proinflammatory changes were accompanied with a prominent increase in apoptotic and necrotic cell death in gingival tissue of IDO knockout mice compared with wild-type mice. CONCLUSION: Collectively, our findings support a major role for IDO in the development of gingival inflammation, as an example of an inflammatory condition, and lay the foundation for subsequent studies to explore it as a novel immunotherapy target.

Accelerated NaCl-induced hypertension in taurine-deficient rat: role of renal function.

Taurine modulates blood pressure and renal function. As the kidney plays a pivotal role in long-term control of arterial pressure, we tested the hypothesis that taurine-deficient rats display maladaptive renal and blood pressure responses to uninephrectomy. Control and taurine-deficient (i.e., beta-alanine-treated) rats with either one or two remaining kidneys were fed diets containing basal or high (8%) NaCl diet. Urine osmolality was greater in the taurine-deficient than controls fed a normal NaCl diet; proteinuria and blood pressure were unaffected by uninephrectomy. Following 6 weeks on an 8% NaCl diet, the uninephrectomized (UNX) animals developed significant hypertension, which was more severe in the taurine-deficient group; baroreflex function was unaffected. However, the UNX taurine-deficient rats displayed impaired ability to dispose of an acute isotonic saline volume load before a switchover to a high NaCl diet. Nonetheless, a more protracted exposure (i.e., 14 weeks) to dietary NaCl excess eliminated the blood pressure differential between the two groups; at this stage, renal excretory responses to an acute saline volume load or to atrial natriuretic peptide were similar in the two groups. Nonetheless, hypertensive taurine-deficient rats displayed greater proteinuria, although both groups excreted proteins of similar molecular weights ( approximately 15-66 kDa). Further, taurine-deficient kidney specimens displayed periarterial mononuclear cell infiltrates with strong immunoreactivity to the histiocyte marker CD68, suggestive of increased phagocytic activity. In conclusion, taurine deficiency modulates renal adaptation to combined uninephrectomy and dietary NaCl excess, resulting in an accelerated development of hypertension.

Taurine modulates arginine vasopressin-mediated regulation of renal function.

Taurine has been implicated in the regulation of arginine vasopressin (AVP) secretion, and we have previously shown altered renal excretory function in the taurine-depleted rat. To further elucidate the role of taurine in AVP-mediated renal responses, the effects of an antagonist for renal AVP receptors were examined in four groups of conscious rats: control, taurine-supplemented, taurine-depleted, and taurine-repleted. Control and taurine-supplemented rats displayed similar and significant AVP receptor antagonist-induced elevations in fluid excretion, sodium excretion, and free water clearance but a marked reduction in urine osmolality. These effects are consistent with inhibition of endogenous AVP activity. By contrast, in the taurine-depleted rats, the magnitude and the time course of drug-induced renal excretory responses lagged behind those of the control and taurine-supplemented groups. Further, baseline urine osmolality was significantly higher in the taurine-depleted compared with the control or taurine-supplemented groups. However, after administration of the antagonist, taurine-depleted rats manifested a delayed but more marked reduction in urine osmolality, thereby eliminating the baseline differential that existed between the taurine-depleted rats and control or taurine-supplemented groups. Consistent with these observations, plasma AVP was significantly increased in the taurine-depleted compared with the control rats. Interestingly, taurine repletion shifted all responses closer to the control group. Analysis of the data suggests that the effect of the antagonist on renal excretory function is related primarily to altered tubular reabsorption activity. These observations suggest that taurine modulates renal function, and, thereby, body fluid homeostasis, through an AVP-dependent mechanism.

Renal adenosine A3 receptors in the rat: assessment of functional role.

The functional roles of adenosine A3 receptors in the rat kidney were assessed for the first time with respect to A1 receptor-mediated responses. Utilizing a chronically instrumented conscious rat preparation, we tested renal excretory responses to acute administration of the A3 receptor antagonists 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1 ,4-(+)-dihydropridine-3,5-dicarboxylate (MRS-1191) and 9-chloro-2-(2-furyl)-5-phenylacetylamino-[1,2,4]-triazolo[1,5-c]qu inazoline (MRS-1220) with reference to the effects of the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The intravenous administration of DPCPX resulted in significant increases in fluid and sodium excretions without affecting glomerular filtration rate (GFR). This suggests that DPCPX-induced diuretic and natriuretic responses are related to decreased tubular reabsorption. However, neither MRS-1191 nor MRS-1220 alone affected fluid or sodium excretions, or GFR, indicating lack of an effect of either compound on renal function. On the other hand, the co-administration of MRS-1220 with DPCPX abolished both the diuretic and natriuretic responses to DPCPX, being suggestive of antagonism between these two compounds. MRS-1191, however, did not affect the DPCPX-induced fluid and sodium excretions. Neither the A1 nor the A3 receptor antagonists altered potassium excretion individually or in combination. The data suggest that while adenosine A1 receptors are involved in the regulation of renal fluid and sodium transport, A3 receptors do not appear to have a major role in regulation of renal excretory function under baseline physiological conditions.

NaCl-induced hypertensive rat model of non-insulin-dependent diabetes: role of sympathetic modulation.

Systemic hypertension is common in individuals with non-insulin-dependent diabetes (NIDD) and, in this population, markedly increases the risk for cardiovascular complications. The aims of this study were to develop a rat model of combined NaCl-induced hypertension and NIDD, and to determine the contribution of the sympathetic nervous system to the development of the manifest hypertension. Two-day old male Wistar-Kyoto rats were injected with either streptozotocin (90 mg/kg, ip; NIDD) or vehicle (citrate buffer; control). At 4 weeks of age, the animals underwent either a right nephrectomy or a sham operation. Animals in each group were further subdivided, with one group maintained on normal (0.72 %) NaCl diet whereas the other was placed on a high (8%)-NaCl diet. At 6 months of age, diabetes was confirmed by glucose tolerance testing. Hemodynamic parameters were measured in the freely moving animal (ia) before and after the administration of prazosin (peripheral alpha1-adrenergic antagonist, iv) or clonidine (central alpha2-adrenergic agonist). The NIDD rat displayed a higher (P < .05) blood glucose concentration than the nondiabetic control rat during the glucose tolerance test. Elevated dietary NaCl significantly increased mean arterial pressure (MAP) in the uninephrectomized, but not the sham-operated groups. Acute administration of prazosin resulted in a significantly greater reduction in MAP of both hypertensive groups than of their normotensive counterparts. Moreover, clonidine caused a significant reduction in MAP of the hypertensive control rat but not in the normotensive controls. By contrast, both the hypertensive NIDD and the normotensive NIDD rats showed a similar reduction in MAP in response to clonidine administration. The data suggest that the combination of uninephrectomy and dietary NaCl excess confers hypertension on the NIDD rat. Moreover, enhancement of the sympathetic pathway plays an important role in the regulation of arterial pressure in the hypertensive NIDD rat.

Effects of chronic taurine treatment on reactivity of the rat aorta.

The effects of chronic taurine treatment on the reactivity of the aorta form male Wistar-Kyoto rats were investigated. Contractile responses to norepinephrine (NE) and potassium chloride (KCl) were attenuated in aortic rings from taurine-treated rats as compared to controls both in the absence and presence of endothelium. However, the degree of attenuation was greater in endothelium-intact tissues contracted with NE. Acetylcholine (Ach)-induced relaxation responses were augmented in endothelium-intact vessels from rats supplemented with taurine compared to the responses observed in control preparations. Relaxation responses of the aortae from control and taurine-treated rats to sodium nitroprusside (SNP) were not different from each other. Our results suggest that taurine treatment attenuates vascular contractility nonspecifically and this effect is partly mediated via the endothelium.

Cardiovascular responses of the taurine-depleted rat to vasoactive agents.

The objective of this study was to assess the effect of taurine-depletion on cardiovascular responses of rat to vasoactive agents. Male Wistar-Kyoto (WKY) rats were given either tap water (control) or 3% beta-alanine (taurine-depleted) for three weeks. Thereafter, mean arterial pressure (MAP) and heart rate of the freely moving animal were measured in response to vasoactive agents. Administration of phenylephine (5-40 microg/kg/min; i.v.) resulted in a similar and significant increase in MAP but a reduction in heart rate in both control and taurine-depleted groups. On the other hand, administration of sodium nitroprusside (15-300 microg/kg/min; i.v.) elicited a similar and significant reduction in MAP but increased heart rate in both groups. Lack of a differential response to phenylephrine and sodium nitroprusside between the two groups suggests that baroreflex regulation of cardiovascular function is not adversely affected by taurine-depletion. Administration of angiotensin II (0.1-3.0 microg/kg/min; i.v.) resulted in a dose-related increase in the pressor response and a decrease in heart rate in both groups. However, angiotensin II-induced pressor response was reduced in the taurine-depleted compared to the control rats (p < 0.05); heart rate was similarly reduced in both groups. Acute exposure to beta-alanine (3 g/kg; i.v., 30-minutes) did not alter angiotensin II-induced hemodynamic responses. Similarly, incubation of aortic rings with beta-alanine (40mM, 30 minutes) did not affect the contractile responses to angiotensin II. The results suggest that beta-alanine, per se, does not affect angiotensin II-induced responses in rat. However, beta-alanine-induced taurine depletion is associated with a reduction in the pressor response to angiotensin II without impairing baroreflex function.

Lifetime treatment with captopril improves renal function in spontaneously hypertensive rats.

Lifetime treatment with captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). This study tests the hypothesis that compared to untreated hypertensive SHR, captopril-treated SHR display similar diuretic and natriuretic responses to an isotonic saline infusion despite significantly lower arterial pressure. Eight-week-old, male SHR were instrumented with femoral arterial, venous, and bladder catheters. Forty-eight hours later, each rat was infused intravenously with an isotonic saline load (5% of body weight; 0.5 ml/min). Lifetime captopril-treated SHR and untreated control SHR displayed nearly identical natriuretic and diuretic responses to the saline infusion. Thus, although lifetime captopril treatment significantly reduces mean arterial pressure in SHR, renal excretory responses appear to be unaltered. Moreover, histological examination of the kidneys of the lifetime captopril-treated SHR did not reveal significant structural damage in the kidneys at either 8 weeks of age or at 12 months of age. Together, the data suggest that lifetime captopril treatment does not adversely affect renal function and structure in SHR.

Dietary NaCl-induced hypertension in uninephrectomized Wistar-Kyoto rats: role of kidney function.

This study tests the hypothesis that combination of unilateral nephrectomy and a high sodium chloride (NaCl) diet causes hypertension in otherwise normotensive Wistar-Kyoto (WKY) rats and that this hypertensive response is due to a deficit in the remaining kidney's function. Four-week-old male WKY rats underwent either a right nephrectomy or a sham operation. Two weeks later, the groups either were switched to a high (8%) NaCl diet or remained on the basal (0.72%) NaCl diet. At ages 3 and 6 months, hemodynamic parameters and renal excretory responses were measured, in the conscious animals, before and after administration of a 30-min isotonic saline challenge (5% of body weight). The high-NaCl diet increased arterial pressure in the uninephrectomized but not in sham-operated rats; the development of hypertension was associated with increases in baseline renal excretion of fluid and sodium and diuretic and natriuretic responses to the isotonic saline challenge. The increased diuresis and natriuresis in the hypertensive WKY rats were related to a significant reduction in renal tubular reabsorption and an associated increase in fractional excretion of fluid and sodium. The high-NaCl diet also increased renal excretion of fluid and sodium in the sham-operated rats; however, the uninephrectomized animals excreted much more fluid and sodium than did sham-operated rats. These data suggest that the combination of unilateral nephrectomy and dietary NaCl excess causes hypertension in the normotensive WKY rats, but the hypertensive response is not likely due to a functional deficit in the remaining kidney.

Renal excretory responses of taurine-depleted rats to hypotonic and hypertonic saline infusion.

Male Wistar-Kyoto rats were given either tap water (control) or 3% beta-alanine (taurine-depleted) for three weeks. To prepare for the kidney function studies, the animals were then implanted with femoral vessels and bladder catheters. Two days after surgery, each rat was given an intravenous infusion of saline at the rate of 50 microliter/min and urine samples were collected at specific time intervals. An isotonic saline solution (0.9% NaCl) was infused for determination of baseline parameters and was followed by the infusion of a hypotonic saline solution (0.45% NaCl). Two days later, the infusion protocol was repeated in the same animals; however, a hypertonic saline solution (1.8% NaCl) was substituted for the hypotonic saline solution. Renal excretion of fluid and sodium increased in the control, but not taurine-depleted, rats during the hypotonic saline infusion. Interestingly, diuretic and natriuretic responses were similar between the groups during hypertonic saline infusion. The results suggest that taurine-depletion in rats affects renal excretory responses to a hypotonic, but not a hypertonic, saline solution.

Effects of inorganic fluoride on renal excretion of fluid and sodium in diabetic rats.

The hypothesis that the diabetic rat is more susceptible to the adverse renal effects (i.e., urine concentrating defect) of inorganic fluoride was tested by comparing fluid and sodium excretion rates in nondiabetic and diabetic rats before and after fluoride administration. Male Fischer 344 rats were injected with either vehicle (0.1 M citrate buffer, i.v.) or streptozotocin (55 mg/kg body weight). Renal excretions of fluid and sodium were determined in conscious animals following administration (i.v.) of a saline volume load containing or lacking inorganic fluoride (0.2 mg/ml). To examine the effect of fluoride without the contribution of a saline load, renal excretions of fluid and sodium were determined following a gradual, graded elevation in plasma fluoride concentration. The natriuretic and diuretic responses to an isotonic saline load were similar between the groups prior to and after fluoride administration. Graded elevations in the fluoride concentration of plasma mediated a slight increase in fluid and sodium excretion in the control rat while the treatment protocol led to a reduction in fluid excretion and an increase in the sodium excretion in the diabetic rat. As a result, the ratio of sodium/fluid excretion following fluoride administration was significantly higher in the diabetic compared to the control rat. These results suggest a differential effect of inorganic fluoride on the renal excretion of sodium and fluid between the nondiabetic and diabetic rat.

Is there a link between impaired glucose metabolism and protein kinase C activity in the diabetic heart?

The activity of the beta isoform of protein kinase C (PKC beta) is reduced in the diabetic heart. Since this isozyme has been implicated in insulin action, we tested the hypothesis that PKC beta contributes to the development of impaired glucose metabolism by the noninsulin-dependent diabetic heart. Exposure of the diabetic heart to buffer containing the protein kinase C activator, phorbol myristate acetate, increased PKC beta activity in the membrane. Associated with the improvement in PKC beta activity was a biphasic change in glucose metabolism. The initial phase was characterized by a breakdown in glycogen stores, a stimulation in glucose oxidation and a decrease in endogenous fatty acid oxidation. This was followed by a second phase in which the uptake of glucose was modestly stimulated. Nonetheless, since the phorbol ester did not overcome the diabetes-linked defect in pyruvate dehydrogenase, the increase in glycolytic flux was not associated with a rise in glucose oxidation. Consequently, nearly 50% of the triose units were diverted into lactate and pyruvate production and the generation of ATP from glucose was restricted. Since insulin promotes not only glucose uptake, but also glycogen synthesis and glucose oxidation, the phorbol ester and insulin effects are very different. Thus, the data do not support a role for PKC beta in the development of glucose metabolic defects in the hearts of noninsulin-dependent diabetic rats.

Renal responses to hypertonic saline infusion in salt-sensitive spontaneously hypertensive rats.

In Wistar Kyoto (WKY) and Sprague Dawley rats, high dietary sodium chloride (NaCl) increases natriuretic and diuretic responses to acute isotonic saline infusion, but in NaCl-sensitive spontaneously hypertensive rats (SHR-S), a high-NaCl diet causes negligible increases in natriuretic and diuretic responses. To investigate whether this deficit in sodium and fluid excretion in SHR-S is stimulus (volume)-specific or because of a more generalized alteration in renal function, the present study measured, in SHR-S and Wistar Kyoto rats, natriuretic and diuretic responses to a hypertonic saline infusion (the amount of sodium infused was equal to that infused in a previous, isotonic experiment). Eight-week-old Wistar Kyoto rats, SHR-S, and salt-resistant SHR were given a basal (1%) or high (8%)-NaCl diet for 2 weeks. Intravenous infusion of hypertonic saline increased mean arterial pressure and reduced heart rate in all groups. Baseline sodium excretion was lower in SHR-S compared with salt-resistant SHR with either diet, but after infusion of hypertonic saline, all 6 groups displayed significant increases in sodium and fluid excretion, glomerular filtration rate, and effective renal blood flow (ERBF). The percent-sodium excretion in response to hypertonic saline infusion was slightly, but significantly, lower in SHR-S (compared with salt-resistant SHR) for either the basal or the high-NaCl diet. We conclude that renal responses to hypertonic saline infusion are affected minimally in SHR-S compared with salt-resistant SHR or Wistar Kyoto rats. Therefore, the deficits in renal function observed in SHR-S after volume loading are not reflected in a renal deficit to hypertonic saline challenge.

Renal excretory responses to saline load in the taurine-depleted and the taurine-supplemented rat.

Taurine is found in high concentrations in mammalian cells. Despite recognition of its role as an organic osmolyte in the kidney, information regarding its effects on renal fluid and electrolyte excretion is sparse. Therefore, the objective of the first series of experiments was to determine the effects of taurine depletion on renal excretory responses to a saline load. To induce taurine depletion, male Wistar-Kyoto (WKY) rats were treated with tap water containing 3% beta-alanine for 3 weeks. Taurine depletion reduced the initial rates of fluid and sodium excretion after an intravenous saline load. This effect was attributed to taurine depletion since maintenance of the taurine-depleted rats on tap water for 2 days to remove the effects of beta-alanine yielded the same pattern as the taurine-depleted rats exposed to beta-alanine at the time of the experiment. Nonetheless, rats exposed to short-term beta-alanine treatment, which has no influence on kidney taurine content, demonstrated a larger (approximately 25%) natriuretic but not diuretic response to the isotonic saline load than either the control or taurine-depleted rats. These data suggest that beta-alanine-induced inhibition of tubular reabsorption of taurine may result in subsequent excretion of taurine with attendant natriuresis early in the course of beta-alanine treatment. We also tested the hypothesis that taurine potentiates the renal excretory responses to an isotonic saline load in WKY rats. Inclusion of taurine in the infusate significantly increased natriuresis and diuresis after a saline load. This effect was greater in animals fed a basal than a high NaCl diet. Our data support a role for taurine as a natriuretic and diuretic agent.

Renal function in the noninsulin-dependent diabetic rat: effects of unilateral nephrectomy.

A new model of noninsulin-dependent diabetic (NIDD) is described which exhibits more prominent defects in renal function than does the standard neonatal NIDD model. To produce this model, 2-day-old neonatal male Wistar Kyoto (WKY) rats were injected intraperitoneally with streptozotocin (90 mg/kg; NIDD), while their corresponding nondiabetic controls were administered vehicle (citrate buffer, pH: 4.5; control). At 3 weeks of age, the animals were weaned, and 1 week later, under ether anesthesia, the animals underwent a right nephrectomy or a sham operation. Diabetes was confirmed by intraperitoneal administration of a glucose load (2g/kg), which resulted in significantly higher blood glucose concentration in the NIDD, compared to the nondiabetic rats. Surgical reduction of renal mass had no effect on the glycemic response to a glucose tolerance test in either group. Intravenous administration of an isotonic saline load resulted in a similar pattern of enhanced sodium and fluid excretion in the two-kidney sham-operated nondiabetic and NIDD rats. These responses were significantly higher than those observed in their counterparts with one remaining kidney. Yet, the natriuretic and diuretic responses to the saline load were significantly lower in the nephrectomized NIDD, compared to the nephrectomized nondiabetic rats. The glomerular filtration rate was similar in the sham-operated (two kidneys) NIDD and nondiabetic rats. In contrast, both the basal and saline-stimulated glomerular filtration rate were lower in the nephrectomized NIDD rats compared to the nephrectomized nondiabetic group. Mean arterial pressure was similar between the two nephrectomized groups, thereby ruling out a significant contribution from the pressure-diuresis-natriuresis mechanism to the reduction in sodium and fluid excretion in the nephrectomized NIDD rats. Thus, unilateral nephrectomy is an effective method of accelerating the manifestation of NIDD-related renal alterations. The mild, but progressive, nature of diabetes in this model should facilitate the investigation of temporal changes in renal function in NIDDM.

Renal function in spontaneously hypertensive rats with insulin-exacerbated hypertension.

This study tests the hypothesis that in spontaneously hypertensive rats (SHR), insulin decreases natriuresis and diuresis and thereby contributes importantly to the hypertensive response to exogenous insulin administration. Seven week old SHR were given daily subcutaneous injections of either insulin (mixture of 5 U/Kg regular and 10 U/Kg NPH) or vehicle (isotonic saline). Within one week of treatment, systolic arterial pressure (SAP) was significantly higher in the insulin, compared to saline, treated SHR (184.2 +/- 2.5 vs. 158.3 +/- 4.0 mm Hg). However, twenty-four hour sodium and fluid excretion and the natriuretic and diuretic responses to an intravenous saline load were not affected either before or after the insulin-induced exacerbation of hypertension in SHR. Insulin treatment did not affect glomerular filtration rate, effective renal blood flow, or fractional excretion of Na+ or fluid. Therefore, our data do not support a major role for sodium and fluid retention in the insulin-induced exacerbation of hypertension in SHR.

Contribution of the sympathetic nervous system to hypertensive response to insulin excess in spontaneously hypertensive rats.

Our previous studies demonstrate that chronic insulin administration exacerbates hypertension in spontaneously hypertensive rats (SHR). In the present study, we tested the hypothesis that the pressor effect of insulin in SHR is medicated by sympathetic nervous system overactivity. Male SHR (7 weeks old) were given daily subcutaneous injection of insulin or vehicle for 3 days, after which each rat received an intravenous infusion of the peripheral ganglionic blocker hexamethonium. Two days later, in a second experiment, the infusion protocol was repeated with the alpha 2-adrenoceptor agonist clonidine, which more selectively inhibits sympathetic (as compared with parasympathetic) nervous system activity. Insulin treatment for 3 days caused a significant increase in mean arterial pressure (MAP; 164 +/- 2 mm Hg vs. saline control 148 +/- 3 mm Hg), but ganglionic blockade with hexamethonium eliminated the difference in blood pressure (BP) between the insulin-treated and control SHR. Infusion of clonidine significantly reduced MAP in the insulin-treated group to the level of the untreated control SHR, but the infusion did not reduce MAP in the latter group. In a second group of rats, acute administration of prazosin also eliminated the difference in MAP between insulin-treated and control SHR. We conclude that in SHR the sympathetic nervous system contributes importantly to the pressor effect of insulin administration and that this effect may be mediated by the central nervous system.

Contribution of the sympathetic nervous system to salt-sensitivity in lifetime captopril-treated spontaneously hypertensive rats.

OBJECTIVE: To test the hypothesis that, in lifetime captopril-treated spontaneously hypertensive rats (SHR), the sympathetic nervous system contributes importantly to the hypertensive effect of dietary sodium chloride supplementation. METHODS: Male SHR (aged 6 weeks) that had been treated from conception onward with either captopril or vehicle remained on a basal sodium chloride diet or were fed a high sodium chloride diet. After 2 weeks, the rats were subjected to ganglionic blockade and 2 days later, an infusion of clonidine. RESULTS: Lifetime captopril treatment significantly lowered mean arterial pressure in both groups. Intravenous infusion of the ganglionic blocker hexamethonium resulted in a rapid decline in MAP that eliminated the dietary sodium chloride-induced increase in MAP in both groups. Infusion of the central nervous system alpha2-adrenergic receptor agonist clonidine also resulted in a greater reduction in MAP in both groups of SHR that were fed the high (compared with the basal) sodium chloride diet. CONCLUSIONS: In both lifetime captopril-treated and control SHR, the sympathetic nervous system contributes to the pressor effects of a high sodium chloride diet.

Cyclosporine-induced nephrotoxicity in deoxycorticosterone-NaCl treated rats.

This study tested the hypothesis that the adverse effects of cyclosporine (Cy) are accelerated in animals with induced hypertension. Four groups of rats were unilaterally nephrectomized at 5 weeks of age. Two weeks later, two of these groups received implantations of Silastic strips impregnated with deoxycorticosterone acetate (DOCA) and were maintained on 1% saline (DOCA-NaCl); the other two groups served as sham controls. Daily injections of Cy (20 mg/kg) were given to one DOCA-NaCl and one control group. During the initial 3 days, the Cy/DOCA-NaCl treated rats displayed a significant increase in systolic arterial pressure (SAP), but their SAP did not increase significantly thereafter. Cy/DOCA-NaCl treatment caused severe nephrotoxicity 18 days after initiation of treatment, but neither cyclosporine nor DOCA-NaCl treatment alone resulted in morphological renal damage. In Cy/DOCA-NaCl rats, the interstitial spaces between renal tubules were dramatically increased in size and contained abundant bundles of collagenous fibres, deposits of immunoreactive laminin, and infiltrates of mononuclear cells. In a second experiment, bilateral renal denervation prior to treatment did not lessen the Cy-induced renal damage. These results indicate that in the DOCA-NaCl rat, Cy treatment damages the renal cortex in a pattern similar to that observed in humans treated chronically with Cy. Further, the results indicate that an absence of renal innervation does not decrease the nephrotoxic effects of Cy in this rapid onset model.